This project explores pharmacokinetic and pharmacodynamic approaches to developing new treatments for drug dependence and reduction of HIV transmission risk behaviors, with a current focus on cocaine and marijuana dependence. Many subjects are at high risk for contracting and spreading HIV infection. HIV transmission risk behaviors are assessed and HIV testing and risk reduction counseling are offered to all subjects. The pharmacokinetic approach being studied is blunting the rate of onset of drug effect by enhancement of drug metabolism. Rate of onset of drug effect is considered an important influence on the reinforcing effects of drugs, but this has never been systematically studied in humans with stimulants. The influence of rate has treatment implications, in that drugs from the same pharmacologic class but with slower rate of onset may have therapeutic efficacy without themselves inducing addiction. One component of this project is systematically evaluating the influence of dose (10, 25, or 50 mg) and infusion duration (10, 30, or 60 sec) on the effects of IV cocaine in experienced cocaine users. Preliminary findings suggest that many of cocaine's psychological (e.g., computer-administered visual analogue scales for "high," "rush") and physiological (e.g., heart rate, blood pressure, cardiac electrical conduction, cerebral blood flow assessed by transcranial Doppler) effects are both dose- and rate-dependent, correlating with cocaine pharmacokinetics. Enhancement of cocaine metabolism is being studied using butyrylcholinesterase (BChE),a major cocaine-metabolizing enzyme in humans. Increased BChE activity might reduce cocaine concentrations and thus cocaine's effects, with possible therapeutic benefits. In a collaborative study with the Behavioral Pharmacology Section and the National Institute on Aging Gerontology Research Center, rats pretreated with BChE had a 50% reduction in motor activity response to an IP cocaine challenge compared to rats pretreated with saline. BChE itself had no effect on motor activity. BChE-treated rats had 400-fold increases in plasma and 3-fold increases in cerebrospinal fluid BChE activity 24 hours after treatment, suggesting the possibility of persisting effects from a single enzyme administration. Squirrel monkeys pretreated with BChE before a cocaine challenge show a three-fold decrease in peak plasma cocaine concentrations and a parallel increase in concentrations of the cocaine metabolite ecgonine methylester. BChE added to human plasma in vitro produced a dose-dependent decrease in cocaine half-life, further suggesting the important influence of BChE activity on cocaine pharmacokinetics. Pharmacodynamic approaches being used include blockade of relevant neurotransmitter receptors. Current studies, in collaboration with the Chemistry & Drug Metabolism Section, are evaluating the effects in humans of an experimental compound, SR141716A, which acts as an antagonist at the cannabinoid 1 (CB1, marijuana) receptor in the brain, and on its interaction with smoked marijuana. These studies involving acute and chronic antagonist administration will provide information on the behavioral and physiological role of CB1 receptors and their endogenous ligands, and insight into the mechanisms of marijuana's effects.